The common thread for all muscular dystrophies is progressive muscle weakness and degeneration. Regardless of the underlying cause, all people who suffer from this group of diseases can benefit from agents which improve muscle strength and enhance regenerative capacity. The goals of this grant are to identify the best IGF-I isoform to counter weakness and degeneration common to all muscular dystrophies and to develop new strength-promoting therapies based on the endogenously expressed E peptides. To achieve these goals, directed expression of three different IGF-I isoforms will be utilized in two different animals models for muscular dystrophy, and the effects on muscle function, mass, and stabilization will be examined as outcome measures for efficacy. Second, to exclude potentially harmful agents, the effects of IGF-I on the hearts will be examined, and tumorigenicity will be evaluated in the Tg-rasH2 mouse. Next, in vitro studies will be utilized to carefully examine the therapeutic potential of the E-peptide extensions produced by the IGF-I isoforms. The dual approach of in vivo and in vitro experiments will accelerate the identification of novel peptides and help to optimize the IGF-I isoform to counter the common pathologies associated with muscular dystrophy. Relevance: The muscular dystrophies have no established cure, and although the diseases has many different causes, all patients suffer from muscle weakness and fragility. Therefore, there is a significant need to maintain or at least slow the progression of muscle wasting to buy time for an effective therapy to be developed. Growth promoting strategies are one way to combat this loss of muscle strength, and can provide benefit to all people suffering from these muscle diseases.